Kanao Rie, Yokoi Masayuki, Ohkumo Tsuyoshi, Sakurai Yasutaka, Dotsu Kantaro, Kura Shinobu, Nakatsu Yoshimichi, Tsuzuki Teruhisa, Masutani Chikahide, Hanaoka Fumio
Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan; Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan; Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan; Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamada-oka, Suita, Osaka 565-0871, Japan; Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan; Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Tokyo, Japan.
DNA Repair (Amst). 2015 May;29:139-46. doi: 10.1016/j.dnarep.2015.02.006. Epub 2015 Feb 16.
Xeroderma pigmentosum variant (XP-V) is a human rare inherited recessive disease, predisposed to sunlight-induced skin cancer, which is caused by deficiency in DNA polymerase η (Polη). Polη catalyzes accurate translesion synthesis (TLS) past pyrimidine dimers, the most prominent UV-induced lesions. DNA polymerase ι (Polι) is a paralog of Polη that has been suggested to participate in TLS past UV-induced lesions, but its function in vivo remains uncertain. We have previously reported that Polη-deficient and Polη/Polι double-deficient mice showed increased susceptibility to UV-induced carcinogenesis. Here, we investigated UV-induced mutation frequencies and spectra in the epidermal cells of Polη- and/or Polι-deficient mice. While Polη-deficient mice showed significantly higher UV-induced mutation frequencies than wild-type mice, Polι deficiency did not influence the frequencies in the presence of Polη. Interestingly, the frequencies in Polη/Polι double-deficient mice were statistically lower than those in Polη-deficient mice, although they were still higher than those of wild-type mice. Sequence analysis revealed that most of the UV-induced mutations in Polη-deficient and Polη/Polι double-deficient mice were base substitutions at dipyrimidine sites. An increase in UV-induced mutations at both G:C and A:T pairs associated with Polη deficiency suggests that Polη contributes to accurate TLS past both thymine- and cytosine-containing dimers in vivo. A significant decrease in G:C to A:T transition in Polη/Polι double-deficient mice when compared with Polη-deficient mice suggests that Polι is involved in error-prone TLS past cytosine-containing dimers when Polη is inactivated.
着色性干皮病变异型（XP-V）是一种人类罕见的常染色体隐性遗传病，易患阳光诱导的皮肤癌，由DNA聚合酶η（Polη）缺陷引起。Polη催化嘧啶二聚体（最主要的紫外线诱导损伤）的精确跨损伤合成（TLS）。DNA聚合酶ι（Polι）是Polη的旁系同源物，有人认为它参与紫外线诱导损伤后的TLS，但它在体内的功能仍不确定。我们之前报道过，Polη缺陷型和Polη/Polι双缺陷型小鼠对紫外线诱导的致癌作用更敏感。在此，我们研究了Polη和/或Polι缺陷型小鼠表皮细胞中紫外线诱导的突变频率和谱。虽然Polη缺陷型小鼠的紫外线诱导突变频率显著高于野生型小鼠，但在有Polη存在的情况下，Polι缺陷并不影响突变频率。有趣的是，Polη/Polι双缺陷型小鼠的突变频率在统计学上低于Polη缺陷型小鼠，尽管仍高于野生型小鼠。序列分析表明，Polη缺陷型和Polη/Polι双缺陷型小鼠中大多数紫外线诱导的突变是二嘧啶位点的碱基替换。与Polη缺陷相关的G:C和A:T对处紫外线诱导突变的增加表明，Polη在体内有助于通过含胸腺嘧啶和胞嘧啶的二聚体进行精确的TLS。与Polη缺陷型小鼠相比，Polη/Polι双缺陷型小鼠中G:C到A:T转换的显著减少表明，当Polη失活时，Polι参与通过含胞嘧啶二聚体的易错TLS。
